tbuckley/cabot-search huggingface dataset:
Structural and social determinants of mental health inequities among collegiate athletes during the COVID-19 pandemic
Authors: Emily Kroshus, Lydia Bell, Kelsey Gurganus-Wright, Brian Hainline
Journal: British Journal of Sports Medicine (2023)

To characterise psychological distress during the COVID-19 pandemic among collegiate athletes and assess whether racial and ethnic differences in psychological distress are attenuated when accounting for inequitable exposure to structural and social determinants of health.Participants were collegiate athletes on teams competing in the National Collegiate Athletic Association (n=24 246). An electronic questionnaire was distributed by email, open for completion 6 October to 2 November 2020. Multivariable linear regression models were used to assess the cross-sectional associations between meeting basic needs, death or hospitalisation due to COVID-19 of a close contact, race and ethnicity, and psychological distress.Athletes racialised as Black had higher levels of psychological distress than their white peers (B=0.36, 95% CI 0.08 to 0.64). Psychological distress was higher among athletes who had more difficulties meeting basic needs, and who had a close contact die or be hospitalised with COVID-19. After adjusting for these structural and social factors, Black athletes experienced less psychological distress than white peers (B=-0.27, 95% CI -0.54 to -0.01).The present findings provide further evidence of how inequitable structural and social exposures are associated with racial and ethnic differences in mental health outcomes. Sports organisations should ensure the mental health services available for their athletes are appropriate for meeting the needs of individuals experiencing complex and traumatic stressors. Sports organisations should also consider whether there are opportunities to screen for social needs (eg, related to food or housing insecurity), and to connect athletes with resources to help meet those needs.
The Notch signaling pathway: a potential target for cancer immunotherapy
Authors: Xinxin Li, Xianchun Yan, Yufeng Wang, Balveen Kaur, Hua Han, Jianhua Yu
Journal: Journal of Hematology & Oncology (2023)

Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications
Authors: Qian Zhong, Xina Xiao, Yijie Qiu, Zhiqiang Xu, Chunyu Chen, Baochen Chong, Xinjun Zhao, Shan Hai, Shuangqing Li, Zhenmei An, Lunzhi Dai
Journal: MedComm (2023)

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain and long-chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.
“<i>To feel supported in your community is to feel loved</i>”: Cultivating community and support for Black transmasculine people navigating anti-Black racism, transphobia, and COVID-19 pandemic
Authors: Gabriel M. Lockett, Kirsten G. Klein, Jordan Mike, Jules P. Sostre, Roberto L. Abreu
Journal: International Journal of Transgender Health (2023)

Black transmasculine people are disproportionately affected by a myriad of intersecting stressors including racism (specifically anti-Black racism), sexism, and cissexism. Black transmasculine people are exposed daily to systemic oppression such as transphobia, dehumanization, and violence, making this community more vulnerable to mental health and physical health concerns. These experiences are further compounded by the lack of relevant research about the unique experiences of Black transmasculine people during the COVID-19 pandemic.
Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase–deficient renal cell carcinoma
Authors: Jiayu Liang, Guangxi Sun, Xiuyi Pan, Mengni Zhang, Pengfei Shen, Sha Zhu, Jinge Zhao, Linmao Zheng, Junjie Zhao, Yuntian Chen, Xiaoxue Yin, Junru Chen, Xu Hu, Yuhao Zeng, Jianhui Chen, Yongquan Wang, Zhihong Liu, Jin Yao, Minggang Su, Rui Huang, Banghua Liao, Qiang Wei, Xiang Li, Qiao Zhou, Jiyan Liu, Yali Shen, Zhenhua Liu, Ni Chen, Hao Zeng, Xingming Zhang
Journal: Genome Medicine (2023)

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear.
TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis
Authors: Hélène Larrue, Gennaro D’Amico, Pol Olivas, Yong Lv, Theresa Bucsics, Marika Rudler, Tilman Sauerbruch, Virginia Hernandez-Gea, Guohong Han, Thomas Reiberger, Dominique Thabut, Jean-Pierre Vinel, Jean-Marie Péron, Juan-Carlos García-Pagán, Christophe Bureau
Journal: Journal of Hepatology (2023)
Affordable oral proinsulin bioencapsulated in plant cells regulates blood sugar levels similar to natural insulin
Authors: Henry Daniell, Rahul Singh, Venkata Mangu, Smruti K. Nair, Geetanjali Wakade, Nataliya Balashova
Journal: Biomaterials (2023)

Diabetes Mellitus is a silent epidemic affecting >500 million, which claimed 6.7 million lives in 2021, a projected increase of >670% in <20 years old in the next two decades but insulin is unaffordable for the large majority of the globe. Therefore, we engineered proinsulin in plant cells to facilitate oral delivery. Stability of the proinsulin gene and expression in subsequent generations, after removal of the antibiotic-resistance gene, was confirmed using PCR, Southern and western blots. Proinsulin expression was high (up to 12 mg/g DW or 47.5% of total leaf protein), stable up to one year after storage of freeze-dried plant cells at ambient temperature and met FDA regulatory requirements of uniformity, moisture content and bioburden. GM1 receptor binding, required for uptake via gut epithelial cells was confirmed by pentameric assembly of CTB-Proinsulin. IP insulin injections (without C peptide) in STZ mice rapidly decreased blood glucose level leading to transient hypoglycemia, followed by hepatic glucose compensation. On the other hand, other than the 15-min lag period of oral proinsulin (transit time required to reach the gut), the kinetics of blood sugar regulation of oral CTB-Proinsulin in STZ mice was very similar to naturally secreted insulin in healthy mice (both contain C-peptide), without rapid decrease or hypoglycemia. Elimination of expensive fermentation, purification and cold storage/transportation should reduce cost and increase other health benefits of plant fibers. The recent approval of plant cell delivery of therapeutic proteins by FDA and approval of CTB-ACE2 for phase I/II human clinical studies augur well for advancing oral proinsulin to the clinic.
Anthracyclines and Biomarkers of Myocardial Injury
Authors: Michael Mallouppas, Robin Chung, Arjun K. Ghosh, Alison Macklin, Derek M. Yellon, J. Malcolm Walker
Journal: JACC CardioOncology (2023)

Remote ischemic conditioning (RIC) has been beneficial in laboratory studies of anthracycline cardiotoxicity, but its effects in patients is not established.The authors studied the effect of RIC on cardiac biomarkers and function during and after anthracycline chemotherapy.The ERIC-Onc study (Effect of Remote Ischaemic Conditioning in Oncology Patients; NCT02471885) was a randomized, single-blind, sham-controlled study of RIC at each chemotherapy cycle. The primary endpoint was troponin T (TnT) during chemotherapy and up to 1 year. Secondary outcomes included cardiac function, major adverse cardiovascular events (MACE), and MACE or cancer death. Cardiac myosin-binding-protein C (cMyC) was investigated in parallel with TnT.The study was prematurely halted after the evaluation of 55 patients (RIC n = 28, sham n = 27). Biomarkers increased from baseline to cycle 6 of chemotherapy for all patients (median TnT 6 [IQR: 4-9] ng/L to 33 [IQR: 16-36)] ng/L; P ≤ 0.001; cMyC 3 (IQR: 2-5) ng/L to 47 (IQR: 18-49) ng/L; P ≤ 0.001). Mixed-effects regression analysis for repeated measures showed no difference in TnT between the 2 groups (RIC vs sham, mean difference 3.15 ng/L; 95% CI: -0.04 to 6.33; P = 0.053), or cMyC (RIC vs sham, mean difference 4.17 ng/L; 95% CI: -0.12 to 8.45; P = 0.056). There were more MACE and cancer deaths in the RIC group (11 vs 3; HR: 0.25; 95% CI: 0.07-0.90; P = 0.034), with more cancer deaths (8 vs 1; HR: 0.21; 95% CI: 0.04-0.95; P = 0.043) at 1 year.TnT and cMyC significantly increased during anthracycline chemotherapy with 81% having a TnT ≥14 ng/L at cycle 6. RIC did not affect the rise in biomarkers, but there was a small increase in early cancer deaths, possibly related to the greater proportion of patients with metastatic disease randomized to the RIC group (54%vs 37%). (Effect of Remote Ischaemic Conditioning in Oncology Patients [ERIC-ONC]; NCT02471885).
The landscape of somatic mutations in lymphoblastoid cell lines
Authors: Madison Caballero, Amnon Koren
Journal: Cell Genomics (2023)

Somatic mutations have important biological ramifications while exerting substantial rate, type, and genomic location heterogeneity. Yet, their sporadic occurrence makes them difficult to study at scale and across individuals. Lymphoblastoid cell lines (LCLs), a model system for human population and functional genomics, harbor large numbers of somatic mutations and have been extensively genotyped. By comparing 1,662 LCLs, we report that the mutational landscape of the genome varies across individuals in terms of the number of mutations, their genomic locations, and their spectra; this variation may itself be modulated by somatic trans-acting mutations. Mutations attributed to the translesion DNA polymerase η follow two different modes of formation, with one mode accounting for the hypermutability of the inactive X chromosome. Nonetheless, the distribution of mutations along the inactive X chromosome appears to follow an epigenetic memory of the active form.
Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial
Authors: Tulika Ranjan, Soma Sengupta, Michael J. Glantz, Richard M. Green, Alexander Yu, Dawit Aregawi, Rekha Chaudhary, Ricky Chen, Mario Zuccarello, Christine Lu-Emerson, Hugh D. Moulding, Neil Belman, Jon Glass, Aaron Mammoser, Mark Anderson, Jagan Valluri, Nicholas Marko, Jason Schroeder, Steven Jubelirer, Frances Chow, Pier Paolo Claudio, Anthony M. Alberico, Seth T. Lirette, Krista L. Denning, Candace M. Howard
Journal: Cell Reports Medicine (2023)

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors.In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2–14.7) compared with 9 months (95% CI, 4.2–13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24–0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.
Cell-type specificity of the human mutation landscape with respect to DNA replication dynamics
Authors: Madison Caballero, Dominik Boos, Amnon Koren
Journal: Cell Genomics (2023)

The patterns of genomic mutations are associated with various genomic features, most notably late replication timing, yet it remains contested which mutation types and signatures relate to DNA replication dynamics and to what extent. Here, we perform high-resolution comparisons of mutational landscapes between lymphoblastoid cell lines, chronic lymphocytic leukemia tumors, and three colon adenocarcinoma cell lines, including two with mismatch repair deficiency. Using cell-type-matched replication timing profiles, we demonstrate that mutation rates exhibit heterogeneous replication timing associations among cell types. This cell-type heterogeneity extends to the underlying mutational pathways, as mutational signatures show inconsistent replication timing bias between cell types. Moreover, replicative strand asymmetries exhibit similar cell-type specificity, albeit with different relationships to replication timing than mutation rates. Overall, we reveal an underappreciated complexity and cell-type specificity of mutational pathways and their relationship to replication timing.
NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma
Authors: Christie P.M. Verkleij, Kristine A. Frerichs, Marloes E.C. Broekmans, Carolien Duetz, Chloe A. O’Neill, Wassilis S.C. Bruins, Paola M. Homan-Weert, Monique C. Minnema, Mark-David Levin, Annemiek Broijl, Gerard M.J. Bos, Marie José Kersten, Saskia K. Klein, Medya M. Shikhagaie, Tineke Casneuf, Yann Abraham, Tina Smets, Greet Vanhoof, Diana Cortes-Selva, Laure van Steenbergen, Elena Ramos, Raluca I. Verona, Maria Krevvata, Pieter Sonneveld, Sonja Zweegman, Tuna Mutis, Niels W.C.J. van de Donk
Journal: HemaSphere (2023)

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 + and granzyme B + NK cells, and higher frequency of TIM-3 + and HLA-DR + NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.
Author Correction: Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination
Authors: Norihide Jo, Yu Hidaka, Osamu Kikuchi, Masaru Fukahori, Takeshi Sawada, Masahiko Aoki, Masaki Yamamoto, Miki Nagao, Satoshi Morita, Takako E. Nakajima, Manabu Muto, Yoko Hamazaki
Journal: Nature Aging (2023)

In the version of this article initially published, two transcriptional errors were present in the Results subsection "Lower CXCR3 + T FH cell induction is correlated with lower IgG levels in older adults."Starting from the fifth sentence in the right-hand column on page 84, the values " 18,200 (5,845)" and "27,200 (7,850)" have been replaced with "11,400 (12,645)" and "19,000 (16,
Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases
Authors: Paul J. Sampognaro, Shruti Arya, Giselle M. Knudsen, Emma L. Gunderson, Angelica Sandoval-Perez, Molly Hodul, Kathryn Bowles, Charles S. Craik, Matthew P. Jacobson, Aimee W. Kao
Journal: Molecular Neurodegeneration (2023)

Abstract Background Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. Results To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. Conclusions Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.
Sutimlimab for the Treatment of Cold Agglutinin Disease
Authors: Sigbjørn Berentsen
Journal: HemaSphere (2023)

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia and a bone marrow clonal lymphoproliferative disorder. Hemolysis in CAD is complement-dependent and mediated by the classical activation pathway. Patients also frequently suffer from fatigue and cold-induced circulatory symptoms. Although not all patients need treatment, the symptom burden has previously been underestimated. Effective therapies target the clonal lymphoproliferation or the complement activation. Sutimlimab, a humanized monoclonal IgG4 antibody that binds and inactivates complement protein C1s, is the most extensively investigated complement inhibitor for the treatment of CAD. This review addresses the preclinical studies of sutimlimab and the studies of pharmacokinetics and pharmacodynamics. We then describe and discuss the prospective clinical trials that established sutimlimab as a rapidly acting, highly efficacious, and low-toxic therapeutic agent. This complement inhibitor does not improve the cold-induced circulatory symptoms, which are not complement-mediated. Sutimlimab is approved for the treatment of CAD in the US, Japan, and the European Union. A tentative therapeutic algorithm is presented. The choice of therapy for CAD should be based on an individual assessment, and patients requiring therapy should be considered for inclusion in clinical trials.